Platelets play a central role in hemostasis and thrombosis, initiating clot formation in response to vessel wall damage. Platelets can also form pathological thrombus and the resulting arterial occlusion can lead to myocardial infarction or stroke. The platelet membrane glycoprotein αIIbβ3 (also called GPIIbIIIa) complex is a member of the integrin family of adhesion receptors. The αIIbβ3 glycoprotein plays a critical role in platelet aggregation, a process that requires the agonist-induced binding of fibrinogen to αIIbβ3. Agonists activate αIIbβ3, presumably by inducing a conformational change that exposes a binding site for fibrinogen, thus enabling fibrinogen to bind in a calcium-dependent manner. Once fibrinogen is bound, platelets can aggregate.
The platelet surface receptor αIIbβ3 is a known therapeutic target and αIIbβ3 agonists are used as therapeutic agents. Antagonists of αIIbβ3 can halt, or even reverse, the progression of nascent thrombus formation in both the coronary and cerebral circulations, particularly when administered intra-arterially. Very early use of αIIbβ3 antagonists can also induce coronary artery reperfusion in patients with acute myocardial infarction. Currently available αIIbβ3 antagonists target the fibrinogen binding site on αIIbβ3. However, current anti-αIIbβ3 agents can cause fatal hemorrhage and attempts to develop oral αIIbβ3 antagonists have failed due to lack of efficacy, increased hemorrhage, thrombocytopenia and an increase in mortality. It has been hypothesized that these oral agents caused conformational changes in αIIbβ3 that resemble receptor activation. Therefore, development of oral αIIbβ3 antagonists that do not induce the active conformation of the receptor will have advantages over the currently available agents.
In light of this, compositions and methods that modify post-translational processing and trafficking of αIIbβ3 in the megakaryocyte, would overcome the shortcomings of currently available therapeutic agents, and would therefore be desirable.